Diabetes mellitus is a major health care problem not only in the developing countries but also in the developed countries The main therapeutic goal in Type 2 Diabetes Mellitus (DM) ie non-insulin dependent Diabetes Mellitus is to control hyperglycemia which is due to derangement's of insulin resistance & impaired insulin secretion, altered lipemia, affected glucose metabolism and other factors & prevent hypoglycemia due to drug therapy.
It has now been proved that combination therapy with two or more antidiabetic agents belonging to different class often results in dramatic improvement in glycemic control, and a better control can be achieved through combination therapy compared to using a large dose of single active ingredient. A combination of antidiabetic agents results in additive or synergistic therapeutic effect, which can restore glucose control when one single agent alone is not successful. Accordingly, such combinations are useful in treating diabetes and associated complications.
Thiazolidinediones such as Pioglitazone HCl is a new class of compounds and are insulin sensitivity enhancers. The plasma elimination half-life (t½) for Pioglitazone HCl at steady state concentrations is 3.3-4.9 hours. The metabolites of Pioglitazone HCl are active in-vivo. Hence, for total Pioglitazone HCl (parent drug and metabolites) the t½ is 16 to 24 hours [Gillies P S & Dunn C J. Drugs 2000; 60(2): 333-343].
Biguanide, in particular Metformin HCl, increases the sensitivity to insulin in peripheral tissues of the hosts. Metformin HCl is also involved in inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis, and inhibition of fatty acid oxidation. It has an absolute oral bioavailability of 40 to 60% and gastro-intestinal absorption is apparently complete within 6 hours of the ingestion. An inverse relation is observed between the dose ingested and the relative absorption with the therapeutic doses of ranging from 0.5 to 1.5 gm, suggesting the involvement of active, saturable absorption process.
The plasma half-life of Metformin HCl is 1.5-4.9 hours [Bailey C J et al. New Eng. Journal of Medicine 1996; 334: 574-579]. Suitable dosage regimens of Metformin HCl include unit doses of 500 mg two to three time's daily and can even be build upto five times daily or 850 mg once or twice daily. [Martindale, The Complete Drug Reference. Sweetman S. C. (Ed) 33rd Ed 2002]
Metformin HCl and Pioglitazone HCl have differing mode of peripheral action, which leads to synergy of drug action and better control of diabetic state. Multiple dosing regimens together, along with large doses, dose dependent absorption, poor bioavailability of Metformin HCl are not preferred since it leads to patient non-compliance, potential side effects & danger of overdosing. It is therefore imperative to shift from multiple dosing to once-a-day or twice-a-day dosing regimens. Longer plasma elimination half-life of Pioglitazone HCl substantiates the recommendation of once daily dosing regimen of Pioglitazone HCl.
The need has therefore been to provide formulations and processes to deliver the active pharmaceutical ingredients ensuring prolonged release of Metformin HCl and instant release Pioglitazone HCl from the formulation when consumed.